N, n-diemthyl-n&#39;-benzyl-n&#39;-(2-thiazolyl)-ethylene-diamines



Patented May 4, 1948 UNITED STATES PATENT orr cs N ,N-DIMETHY L-N' -BENZYL -N (Z-THI- AZOLYL) -ETHYLEN E-DIAMIN ES Clarence W. Sondern, Mendham,

Breivogel, Glen Ridge,

and Philip J.

N. J., assilnors to White Laboratories, Incorporated; Newark, N. J., a corporation of New Jersey No Drawing. Original application January 2,

1947, Serial No.

Divided and this application January 4, 1947, Serial No. 720,318 3 Claims. (Cl. 260-302) This invention relates to anti-histamine compounds, particularly to the preparation of a new compound, N.N-dimethyl-N'-benzyl-N'(2-thiazolyD-ethylenedia-mine and of salts thereof having anti-histamine properties.

It is known that, fundamentally, clinical manifestations of many allergies are due to tissue liberation of histamine brought about by the offending allergens. In the attempt to relieve such .clinical manifestations, it has been proposed to administer compounds to the allergic individual which antagonize or counteract the physio-pathological eilects of histamine. Such compounds are referred to as anti-histamine compounds.

I Although some progress has been made in this field, there has heretofore been discovered no from the alkalized reaction mixture with ether compound which is highly effective and which is reasonably free from undesirable toxic effects.

The advantages of a compound or product which could be administered safely and conveniently to an individual suffering from an allergy due to histamine and which could successfully overcome this condition are apparent.

It is, therefore, an object of the present invention to provide a new and useful therapeutic agent.

An additional object is to provide a therapeutic agent for combattlng allergic conditions due to histamine sensitivity.

A further object is to provide a substance passessing a low degree of toxicity and suitable for therapeutic use.

It has now been found that the heretofore undescribed compound, N,N-dimethyl-N'-benzyl- N'-(Z-thiazolyl)-ethylenediamine, and its salts with acids are efiective agents in combatting allergic conditions due to histamine when administered in dosage forms such as tablets, capsules, elixir, syrup or tincture. The free diamine has the structural formula:

CuHt

HC---N a, V on, H -1 ICH:CH:-N

\ S CH:

and is formed readilyvby reacting together a 2-halothiazole and N,N-dimethyl-N'-benzylethylenediamine in the presence of a dehydrohalogenating. agent; such as pyridine. Following the condensation the product may be isolated in any convenient manner e. g., by concentrating the reaction mixture to a small volume, extracting with ether and distilling the extract.

N,N-dimethyl-N' benzyl NT-(Z-thiazolyD- picrate melting at 162 and distillation of the extract. -N,N-dimethyl- N'-benzyl-ethylenediamine is a substantially colorless oil boiling at 121 to 123 C. at 9 millimeters pressure and having an index of refractionN of 1.507. The picrate melts at 162 to 164 C.

This application is a division of a concurrently filed co-pending application, Serial No. 720.317.

Certain advantages of the invention are apparent from the following examples which are given by way of illustration only and are not to be construed as limiting.

Example 1.-N,N-dimethyl N-benzyl-ethylenediamine A solution of 108 grams of beta-dimethylaminoethyl chloride in 125 milliliters of ether was added over a period of one-half hour and with rapid stirring to a solution of 108 grams of benzyl amine and 98 grams of potassium acetate in 500 milliliters of alcohol maintained at about 30 C. Stirring Was continued at 30 C. for an additional two hours and then for six and one- I half hours at 45 to .50 C. After standing overnight at room temperature, the mixture was acidified to Congo red with concentrated aqueous hydrochloric acid, about milliliters being re- 'quired. The mixture was cooled to room temperature and the precipitated potassium chloride was removed by filtering and washing the residue with 715 milliliters of alcohol. The combined filtrate and washings were concentrated to 300 milliliters.

150 grams of potassium hydroxide was added and the mixture extracted with 600 milliliters of ether. The ethereal extract was dried over solid potassium hydroxide, the ether evaporated and the oily residue distilled in vacuo.. The fraction distilling at 121 to 123C. at 9 millimeters pressure weighed 33 grams and was practically pure N,N-dimethyl-N'-benzyl ethylenediamine. The product was a colorless, oily liquid having an index of refraction N of 1.507. It formed a to 164 C.

' then removed by 3' Example 2.N,N-dimethfll-N-benzul-N'-(Z-thiaeolul) -ethulenediamine A mixture of grams of z-bromothiazole, grams or N,N-dimethyl-N'-benzyl-ethylenediamine and 35 grams of pyridine was refluxed for 8 hours. The temperature of the liquid during refluxing was about 142 C. The pyridine was distillation in vacuo until the vapor temperature rose to at'30 millimeters. The residue from the distillation was cooled to room temperature, rendered alkaline by adding 50 milliliters of 20 per cent aqueous sodium hydroxide solution and the mixture then extracted with 300 milliliters of ether. The ethereal extract was dried over anhydroussodiumcarbonate and the ether removed by distillation. The dark, oily residue was then distilled invacuo and the fraction which boiled at to C. at 15 millimeters was collected separately. This fraction weighed 14.6 grams and consisted principally oi. N.N dimethyl-N'-benzyl-N'-(il-thiazolyl) -ethylenediamine. The base was purified by conversion to the picrate which. after recrystallization from methanol, melted at 138 to 141 C. The free base was isolated from the picrate by treating the latter with aqueous sodium hydroxide, extracting the mixture with ether and distilling the ether. 1

- '4 The hydrochloride was prepared as follows: Alter isolation from the picrate. 10.1 grams of the free base was dissolved in 10 milliliters of anhydrous'alcohol and 13.9 milliliters of alcoholic hydrochloric acid (100 milliiiters=10 grams 1101 added. The clear solutionwas concentrated to 20 milliliters and the monohydrochloride precipitated by the addition oi acetone. The total yield of monohydrochloride was-10.4 grams. This was recrystallized first from a mixture of two parts of ethyl acetate, and one part of anhydrous alcohol, and then from n-butanol. The yield of pure monohydrochloride was 8.4 grams. This corresponded to a yield of 17.5 per cent, based on the I z-bromothiazole used.

Anal: Calc'd for CuHuNaSCL-C, 56.41; H. 6.77; N. 14.10; B, 10.76; Cl, 11.90. Found: C. 56.48; H, 6.86; N, 14.29; s. 10.54; C1, 12.11.

We claim:

1. A compound selected from the class consisting of N,N-dimethyl-N-benzyl-N'-(2-thiazolyl)- ethylenediamine and salts thereof. 2. N,N dimethyl N'- benzyl-N' (z-thiazolyl) ethylenediamine.

3. N,N dimethyl N'- benzyl-N'-(2-thiazolyl) ethylenediamine monohydrochloride.

' CLARENCE W. SONDERN.

PHILIP J. BREIVOGEL. 

